ABSTRACT Almost 30% of patients with major depressive disorder have a chronic illness that is treatment refractory. Vagus nerve stimulation (VNS) has recently been approved by the FDA for treatment refractory depression. However, there have been few pre-clinical studies addressing the central actions of VNS that may be relevent for its antidepressant effect. We completed recently some preliminary studies in which VNS was administred either acutely or chronically to non-anesthetized rats using clinically-relevant stimulation parameters. Both functional neuroanatomical and behavioral effects were observed. The goal of this proposal is to expand and amplify these observations so as to evaluate more comprehensively effects produced by VNS in brain and the mechanisms underlying such effects. Our overall hypothesis is that VNS produces its beneficial clinical effects, as measured by reduced immobility in the forced swim test (FST) in rats, by activation of multiple neurotransmitter/neuromodulator systems in brain, in particular serotonin or norepinephrine and/or brain- derived neurotrophic factor containing neurons (through phosphorylation of TrkB receptors). To test these ideas, we will: (1) initially optimize stimulation parameters, using both acute and chronic (3 week) VNS by determining behavioral effects it produces in the FST and compare its effects to those produced by the selective noradrenergic reuptake inhibitor, desipramine, and the selective serotonin reuptake inhibitor, sertraline, (2) use the chronic VNS protocol that has the best effect in the FST to measure its effects on c-Fos, FosB, Egr-1, activation of TrkB, 1-adrenoceptors, and somatodendritic 5-HT autoreceptor sensitivity and compare results to those caused by chronic treatment with desipramine or sertraline, and (3) test the role of norepinephrine and serotonin in the antidepressant-like effect of chronic VNS, desipramine and sertraline by lesioning rats with either 6-hydroxydopamine or 5,7- dihyroxytryptamine. Immunohistochemistry will be used to measure c-Fos, FosB, Egr-1, and phosphorylated TrkB. Quantitative autoradiography will be used to measure 1-adrenoreceptors. DPAT-induced changes in extracellular 5-HT in the striatum will be used as an index of autoreceptor sensitivity. The results could provide important, new information regarding the central nervous system effects of VNS that are important for the treatment of depression. PROJECT NARRATIVE About 30% of patients with major depressive disorder are resistant to standard antidepressant therapy. Vagal nerve stimulation (VNS) was approved recently for such refractory patients; it is moderately effective, but how it works is unknown. Our studies will evaluate comprehensively effects produced by VNS in the brain of rats and the mechanisms underlying such effects, so as to provide data to allow VNS to become even more effective.